Disruption of synaptic transmission in the Bed Nucleus of the Stria Terminalis reduces seizure-induced death in DBA/1 mice and alters brainstem E/I balance

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Accumulating evidence from recent human studies and animal models suggests that seizure-related respiratory arrest may be important for initiating cardiorespiratory arrest and death. Prior evidence suggests that apnea onset can coincide with seizure spread to the amygdala and that stimulation of the amygdala can reliably induce apneas in epilepsy patients, potentially implicating amygdalar regions in seizure-related respiratory arrest and subsequent postictal hypoventilation and cardiorespiratory death. This study aimed to determine if an extended amygdalar structure, the dorsal bed nucleus of the stria terminalis (dBNST), is involved in seizure-induced respiratory arrest (S-IRA) and death using DBA/1 mice, a mouse strain which has audiogenic seizures and a high incidence of postictal respiratory arrest and death. The presence of S-IRA significantly increased c-Fos expression in the dBNST of DBA/1 mice. Furthermore, disruption of synaptic output from the dBNST via viral-induced tetanus neurotoxin significantly improved survival following S-IRA in DBA/1 mice without affecting baseline breathing or hypercapnic and hypoxic ventilatory response. This disruption in the dBNST resulted in changes to the balance of excitatory/inhibitory synaptic events in the downstream brainstem regions of the lateral parabrachial nucleus (PBN) and the periaqueductal gray (PAG). These findings suggest that the dBNST is a potential subcortical forebrain site necessary for the mediation of seizure-induced respiratory arrest, potentially through its outputs to brainstem respiratory regions.

The role of neuronal NO synthase in the respiratory effects of TNF-α

It was shown that an increase level of proinflammatory cytokines has a modulating effect on the reflex control of respiration. The aim of this study was to investigate the involvement of neuronal nitric oxide synthase (nNOS) in the mechanisms of the influence of an increased level of Tumor necrosis factor – α (TNF-α) on the hypoxic ventilatory response. To achieve this goal, experiments were carried out on urethane anesthetized rats with intravenous administration of TNF-α before and after pretreatment with 7-nitroindazole specific nNOS inhibitor. The hypoxic ventilation response was assessed by rebreathing with a hypoxic gas mixture before and after administration of TNF-α. We found that TNF-α decreased the ventilatory response to hypoxia. Pretreatment with nNOS inhibitor reduced respiratory effects of TNF-α. Key words: cytokines, TNF-α, hypoxia, chemoreflex, respiration, ventilation, neuronal nitric oxide synthase.

The role of prostaglandins in the realization of respiratory effects of TNF-α in case of hypoxia

At the present time very little is known about interactions between systemic inflammation and control of respiration. The aim of this study was to compare the respiratory effects of the main inflammatory cytokine TNF - α before and after pretreatment with diclofenac, a nonspecific cyclooxygenase (COX) inhibitor. In experiments on anesthetized, tracheostomized rats, pneumotachometry method was used to measure peak airflow and respiratory rate. The ventilatory response to hypoxia was investigated by the rebreathing method. It is shown that an increase in the systemic level of TNF – α causes a significant increase in the minute volume of respiration, tidal volume, the average speed of the inspiratory flow. In contrast the slope of the hypoxic ventilatory response decreased after administration of TNF-α. Diclofenac pretreatment eliminated these respiratory effects of TNF - α. The data indicate that the ability of TNF - α to enhance basal ventilation and to reduce the ventilatory hypoxic response is mediated by the cyclooxygenase pathway. Key words: tumor necrosis factor – α, hypoxia, prostaglandins, peripheral chemoreception, respiration.

Sleep-disordered breathing and ventilatory chemosensitivity in first ischaemic stroke patients: a prospective cohort study

RationaleSleep-disordered breathing (SDB) is highly prevalent after stroke. The clinical and ventilatory chemosensitivity characteristics of SDB, namely obstructive, central and coexisting obstructive and central sleep apnoea (coexisting sleep apnoea) following stroke are poorly described.ObjectiveTo determine the respective clinical and ventilatory chemosensitivity characteristics of SDB at least 3 months after a first ischaemic stroke.MethodsCross-sectional analysis of a prospective, monocentric cohort conducted in a university hospital. 380 consecutive stroke or transient ischaemic attack patients were screened between December 2016 and December 2019.Measurements and main resultsFull-night polysomnography, and hypercapnic ventilatory response were performed at a median (Q1; Q3) time from stroke onset of 134.5 (97.0; 227.3) days. 185 first-time stroke patients were included in the analysis. 94 (50.8%) patients presented no or mild SDB (Apnoea-Hypopnoea Index <15 events/hour of sleep) and 91 (49.2%) moderate to severe SDB, of which 52 (57.1%) presented obstructive sleep apnoea and 39 (42.9%) coexisting or central sleep apnoea. Obstructive sleep apnoea patients significantly differed regarding their clinical presentation from patients with no or mild SDB, whereas there was no difference with coexisting and central sleep apnoea patients. The latter presented a higher frequency of cerebellar lesions along with a heightened hypercapnic ventilatory response compared with no or mild SDB patients.ConclusionSDB in first-time stroke patients differ in their presentation by their respective clinical traits and ventilatory chemosensitivity characteristics. The heightened hypercapnic ventilatory response in coexisting and central sleep apnoea stroke patients may orientate them to specific ventilatory support.

Burrowing star-nosed moles (Condylura cristata) are not hypoxia tolerant

ABSTRACT Star-nosed moles (Condylura cristata) have an impressive diving performance and burrowing lifestyle, yet no ventilatory data are available for this or any other talpid mole species. We predicted that, like many other semi-aquatic and fossorial small mammals, star-nosed moles would exhibit: (i) a blunted (i.e. delayed or reduced) hypoxic ventilatory response, (ii) a reduced metabolic rate and (iii) a lowered body temperature (Tb) in hypoxia. We thus non-invasively measured these variables from wild-caught star-nosed moles exposed to normoxia (21% O2) or acute graded hypoxia (21–6% O2). Surprisingly, star-nosed moles did not exhibit a blunted HVR or decreased Tb in hypoxia, and only manifested a significant, albeit small (&lt;8%), depression of metabolic rate at 6% O2 relative to normoxic controls. Unlike small rodents inhabiting similar niches, star-nosed moles are thus intolerant to hypoxia, which may reflect an evolutionary trade-off favouring the extreme sensory biology of this unusual insectivore.